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Virus-Driven Carcinogenesis

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Virus-Driven Carcinogenesis cancers Review Virus-Driven Carcinogenesis Yuichiro Hatano 1,* , Takayasu Ideta 2,3, Akihiro Hirata 4, Kayoko Hatano 5, Hiroyuki Tomita 1 , Hideshi Okada 6 , Masahito Shimizu 2 , Takuji Tanaka 7 and Akira Hara 1 1 Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; [email protected] (H.T.); [email protected] (A.H.) 2 Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; [email protected] (T.I.); [email protected] (M.S.) 3 Department of Laboratory Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan 4 Laboratory of Veterinary Pathology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1194, Japan; [email protected] 5 Department of Obstetrics and Gynecology, Gifu University Hospital, Gifu 501-1194, Japan; [email protected] 6 Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; [email protected] 7 Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu 500-8513, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-58-230-6225 Simple Summary: Carcinogens, causes of cancer, are usually invisible and therefore in vivo carcino- genesis is difficult to detect. Tumor viruses, definitive carcinogens, are also usually unremarkable, particularly due to latent infection. However, recent developments in tumor virology are unraveling how a single infected cell becomes a life-threatening cell population from a molecular perspective. The recognition and characterization of virus-driven carcinogenesis is the first step in the eradication of tumor virus-associated cancer. Citation: Hatano, Y.; Ideta, T.; Hirata, A.; Hatano, K.; Tomita, H.; Okada, H.; Abstract: Cancer arises from the accumulation of genetic and epigenetic alterations. Even in the era Shimizu, M.; Tanaka, T.; Hara, A. of precision oncology, carcinogens contributing to neoplastic process are still an important focus of Virus-Driven Carcinogenesis. Cancers research. Comprehensive genomic analyses have revealed various combinations of base substitutions, 2021, 13, 2625. https://doi.org/ referred to as the mutational signatures, in cancer. Each mutational signature is believed to arise 10.3390/cancers13112625 from specific DNA damage and repair processes, including carcinogens. However, as a type of carcinogen, tumor viruses increase the cancer risk by alternative mechanisms, including insertional Academic Editor: Karl Munger mutagenesis, viral oncogenes, and immunosuppression. In this review, we summarize virus-driven carcinogenesis to provide a framework for the control of malignant cell proliferation. We first provide Received: 30 April 2021 Accepted: 25 May 2021 a brief overview of oncogenic viruses and describe their implication in virus-related tumors. Next, Published: 27 May 2021 we describe tumor viruses (HPV, Human papilloma virus; HBV, Hepatitis B virus; HCV, Hepatitis C virus; EBV, Epstein–Barr virus; Kaposi sarcoma herpesvirus; MCV, Merkel cell polyoma virus; Publisher’s Note: MDPI stays neutral HTLV-1, Human T-cell lymphotropic virus, type-1) and tumor virus-related cancers. Lastly, we with regard to jurisdictional claims in introduce emerging tumor virus candidates, human cytomegalovirus (CMV), human herpesvirus-6 published maps and institutional affil- (HHV-6) and adeno-associated virus-2 (AAV-2). We expect this review to be a hub in a complex iations. network of data for virus-associated carcinogenesis. Keywords: tumor virus; HPV; HBV; HCV; EBV; KSHV; MCV; HTLV-1; HIV-1 Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article 1. Introduction distributed under the terms and Cancer is classified as a cell proliferative lesion according to its histology and pri- conditions of the Creative Commons mary site. However, cancer frequently shows variation among individuals and unique Attribution (CC BY) license (https:// histological features, and no single histological type is identical to the others. Consistent creativecommons.org/licenses/by/ with this notion, next-generation sequencing-based genomic analyses have shown that 4.0/). Cancers 2021, 13, 2625. https://doi.org/10.3390/cancers13112625 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 2625 2 of 27 each histological cancer type shows intertumoral heterogeneity owing to genomic and epigenomic alterations in cancer-related genes. Such comprehensive analyses clarify not only the status of established cancer-related genes but also collateral factors, including tumor mutational burden and microsatellite instability. These additional factors are closely associated with past DNA damage and repair responses in cancer and play an important role in deciding optimal molecular therapies. These comprehensive analyses allow us to understand individual cancer in a chronological framework and, thus, the molecular classification of cancer is an emerging area in research and healthcare [1]. Will the emerging genomic classification really be the best and only approach in clinical oncology? Another approach for the classification of cancer is to investigate possible predisposing factors. These factors can be hereditary elements [2] and environmental factors, called carcinogens. Among carcinogens, oncogenic viruses predispose carriers to specific types of cancer in infected cells. Of note, studies of virus-driven carcinogenesis have generated insight into oncogenes [3] and thereby to carcinogenesis. Oncogenic viruses are a promising target for cancer prevention, diagnosis, and therapy. In this review, we summarize virus-driven carcinogenesis to understand the malignant cell proliferation as controllable. We initially provide brief remarks on human viruses and oncogenic viruses. Next, we provide a detailed overview of every established virus-driven carcinogenesis. Lastly, we introduce miscellaneous infectious agents, including emerging tumor virus candidates. 2. Overview of Tumor Viruses Inorganic particles that are infectious to humans, called human viruses, were discov- ered at beginning of the 20th century [4]. Despite possessing genetic information like other organisms, viruses fail to self-replicate. Viral replication requires an environmental factor, i.e., an appropriate host cell. Occasionally, virus activity leads to the illness and death of the host, resembling many ecological interactions. Owing to extensive research, the current virus taxonomy is highly complex and is beyond the scope of this review [5]; accordingly, we focus on the relationships between cancer and tumor viruses. Tumor viruses, also called oncogenic viruses or oncoviruses, are associated with one- ninth of cancer cases worldwide [6–9]. As summarized in Table1, principal oncogenic viruses can be classified into six families. The International Agency for Research on Cancer (IARC) recognizes several tumor viruses as human carcinogens [10,11]. Hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV), human papilloma viruses (HPVs), especially type 16, and human T-cell lym- photropic virus, type-1 (HTLV-1) are classified as “carcinogenic to humans“ (Group 1) [10]. Polyoma viruses were later added to the IARC monograph series. Merkel cell polyoma virus (MCV) is classified as “probably carcinogenic to humans” (Group 2A); BK virus and JC virus are classified as “possibly carcinogenic to humans” (Group 2B); SV40 virus is regarded as “not classifiable as to its carcinogenicity to humans”(Group 3) [11]. Recently, evidence for the carcinogenicity of MCV has accumulated [12]. Cancers 2021, 13, 2625 3 of 27 Table 1. Summary of human tumor viruses. Variable HPV HBV HCV EBV KSHV MCV HTLV-1 Kaposi Human Human Epstein–Barr Merkel Cell Full Name/ Hepatitis B Hepatitis C Sarcoma T-cell Lym- Papilloma Virus/ Polyoma synonym Virus Virus Herpes photrophic Virus HHV-4 Virus Virus/HHV-8 Virus, type-1 Family Papillomaviridae Hepadnaviridae Flaviviridae Herpesviridae Herpesviridae Polyomaviridae Retroviridae Baltimore Class I Class VII Class IV Class I Class I Class I Class VI System 1 Virus dsDNA ss/dsDNA +ssRNA lineardsDNA circulardsDNA dsDNA +RNA Genome Genome 8 kbp 3 kb/kbp 9.5–12.5 kb 170 kbp 170 kbp 5.4 kbp 9 kbp Size Virion 52–60 nm 52–55 nm 40–60 nm 200 nm 100–150 nm 40–55 nm 100 nm Size Envelope Absent Present Present Present Present Absent Present Capsid Icosahedral Icosahedral Icosahedral Icosahedral Icosahedral Icosahedral Icosahedral Vaccination Accessible Accessible Inaccessible Inaccessible Inaccessible Inaccessible Inaccessible Anti-viral Not Occasionally Not Not Not Effective Effective treatment established Effective established established established Diagnostic anti-HCV p16 HBs antigen EBER LANA CM2B4 ATLA molecule antibody 1 The details of Baltimore system are found in refs. [13,14]. Abbreviations: ATLA, anti-adult T-cell leukemia/lymphoma antibody; ds, double strands; EBER, EBV-encoded small RNA; LANA, Latency-associated nuclear antigen; ss, single strand; +, positive sense. Evidence for virus-driven carcinogenesis is summarized as follows [15]: the existence of viral DNA in tumor tissues, transformation by viral genes in model systems, generation of a neoplastic phenotype in response to the persistent expression of a vital oncogene or modification of host genes, and epidemiological data indicating that viral infections represent
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